How Antibodies and Enzymes Work

By the mid-1930s, Pauling was beginning to understand that simply
knowing the structures of individual proteins was not enough. The
essence of life resulted not from individual molecules, but from
the interactions between them. How did organisms make offspring
that carried their specific characteristics? How did enzymes
recognize and bind precisely to specific substrate molecules? How
did the body produce antibodies that recognized and bound to
specific foreign, invading antigens? How did proteins, these
flexible, delicate, complex molecules, have the uncanny ability
to recognize and interact with specific molecules?

These questions all fell under the heading of biological
specificity. To this topic Pauling directed much of his attention
during the late 1930s and 1940s. To understand biological
specificity, Pauling decided to work first with antibodies and
antigens, the understanding of which immunologists such as Karl
Landsteiner were beginning to perfect. Pauling met and spoke with
Landsteiner on several occasions, and he began his own research
program in the late 1930s combining Landsteiner's methods
with his own most recent chemical techniques. During a decade of
antibody experiments, carried out through the late 1940s, Pauling
built a detailed picture of the binding of antibody and antigen
at the molecular level.

His findings were surprising. Pauling demonstrated that the
precise binding of antigen to antibody was accomplished not by
typical chemical means, but rather through the shapes of
molecules. He discovered that an antibody fits an antigen as a
glove fits a hand. Their shapes were complementary. When the fit
was tight, the surfaces of antibody and antigen came into very
close contact, making possible the formation of many weak bonds
that operated at close quarters and were relatively unimportant
in traditional chemistry--van der Waals' forces, hydrogen bonds,
and so forth. To work, the fit had to be incredibly precise. Even
a single atom out of place could significantly affect the
binding.

Having demonstrated the importance of complementary structure
with antibodies, Pauling extended his idea to other biological
systems, including the interaction of enzymes with substrates,
odors with olfactory receptors, and even the possibility of genes
composed of two complementary molecules.

Pauling's idea that biological specificity was due in great part
to complementary "fitting" of large molecules to one another was
essential in the development of molecular biology. The path of
his research now formed a broad arc, from early work on the
chemical bond as a determinant of molecular structure; through
finding out the structures of large molecules, first inorganic
substances, then biomolecules; and, finally, to elucidating the interactions
between large biomolecules. By the early 1950s, Pauling felt that
he had discovered the essentials of life at the molecular level.
He was ready for something new.